Flashcards in pharmacogenics Deck (101)
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1
pharmacodynamics
what the drug does to the body
mechanism of effect (action)
sensitivity
responsiveness
2
pharmacokinetics
what the body does to the drug
absorption
distribution
metabolism
excretion
3
central compartment blood and body mass
75% of blood flow, 10% body mass
4
a tissue that accumulates a drug preferentially may
act as a reservoir to maintain the plasma concentration and thus prolong its duration of action
5
Rate of transfer between central and peripheral compartments decreases
with aging !
6
pKa =
the pH at which 50% of a drug will be in its ionized form.
7
Blood brain barrier works by
the limited permeability characteristics of the brain capillaries
8
the only limitation to permeation of the CNS by lipid soluble, non-ionized drugs is
cerebral blood flow
9
Blood brain barrier can be overcome by
administration of large doses
or be disrupted by acute head injury or arterial hypoxemia
10
effect site equilibration time
time it takes from administration of an IV drug to effect of drug
11
Ke0
rate constant of ELIMINATION from EFFECT SITE
12
Vd formula
dose of IV drug / plasma concentration before any has been eliminated
13
volume of distribution is influenced by
1. lipid solubility
2. protein binding
3. molecular size
14
A drug that is not very lipid soluble and highly protein bound
Will not be able to cross membranes (not lipid soluble), will be bound to plasma protein (high protein binding) and therefore will remain mostly in the PLASMA.
So it will have a SMALLER Vd.
15
A lipid-soluble drug that is highly concentrated in tissues with a resulting low plasma concentration
will have a calculated Vd that exceeds total body water
16
Elimination Half Time
the time it takes for the PLASMA CONCENTRATION of a drug to decline 50% during elimination phase
17
Elimination half time is directly proportional to
volume of distribution
18
elimination half time is independent of
dose of drug administered
19
Elimination half time is inversely proportional to
clearance of drug
20
Near total (96.9%) elimination of drug from body requires
5 elimination half times
21
Elimination half life
time it takes to eliminate 50% of drug from BODY after its IV injection
22
Context Sensitive Half Time
time it takes for 50% decrease in plasma concentration of drug AFTER DISCONTINUATION OF IV INFUSION
23
Context sensitive half time depends on
Distribution AND excretion
physiochemical properties of the drug AND length of infusion
24
Context sensitive halftime relates to elimination half time
Context sensitive half time bears no constant relationship to the drugs elimination half-time
25
System absorption depends on
System absorption, regardless of route, depends on the drugs solubility
26
Disadvantages of oral administration
emesis, destruction by enzymes or acidic gastric fluid, irregular absorption with food or other drugs.
27
Principle site of drug absorption after PO administration is
small intestine r/t large surface area
28
changes in pH of GI fluid that favor the presence of a drug in its non-ionized form
favor systemic absorption
(lipid-soluble)
29
First Pass Hepatic Effect happens because
Drugs absorbed in the GI system first enter the portal venous blood and pass through the liver BEFORE entering the systemic circulation [[for delivery to tissue receptors]]
drugs in the liver are extensively metabolized.
30
reason for large differences between bioavailability of PO and IV drugs is
first pass hepatic effect
31
Sublingual/transmucosal administration is characterized by
rapid onset, bypasses the liver so no first pass hepatic effect.
32
Transdermal administration characteristics
provides sustained therapeutic plasma []
absorption occurs along sweat ducts and hair follicles that function as diffusion shunts
33
Things that affect the skin's permeability to drugs
thickness and blood flow
why scopolamine goes behind the ear and not on your hand
34
Rectal administration, proximal vs distal
proximal rectal administration is absorbed by superior hemorrhoid veins to portal vein so FIRST PASS EFFECT.
Distal rectal administration bypasses the portal system
Difference is why drug administration via rectum is unpredictable.
35
Most drugs are present in both
ionized and non-ionized forms.
Because most drugs are WEAK ACIDS OR BASES.
36
ionized fraction of drugs are excreted
by the kidneys unchanged.
37
Degree of ionization depends on
the drugs dissociation constant pK and the surrounding pH
38
Changes in pH can affect
the degree to which a drug ionizes
39
When the pK = pH
50% of the drug is in its ionized form and 50% of the drug is non-ionized (lipid-soluble)
40
Ion trapping
ex. when a (basic) drug as lipid-soluble version crosses a membrane to a different environment (more acidic) and then ionizes.
Now ionized form is trapped on one side o membrane and also causes a concentration gradient for more of the drug to cross the membrane.
ex. placenta
41
Protein binding is inversely proportional to
Volume of distribution
42
Unbound drugs in the plasma are more
easily metabolized and excreted
43
Protein binding of drugs facilitates
elimination,
44
Alterations in protein binding are more important for drugs that are
Highly protein bound (94 vs 96 compared to 70 vs 68)
45
Low plasma concentration of drugs aren like to be more
highly protein bound than are higher plasma concentrations of the same drug
46
Renal failure may decrease
the fraction of a drug bound to protein even in the absence of changes in plasma concentrations of albumin or other proteins.
--> something the kidneys usually excrete competes for binding sites on albumin
47
clearance is defined as
volume of plasma cleared of drug by metabolism and excretion
volume of plasma cleared of drug per unit time
48
almost all drugs administered in therapeutic dose range are cleared by
first order kinetics
(at a rate proportional to the amount of drug present in the plasma)
49
Non organ clearance mechanisms
Hofmann Elimination and ester hydrolysis. Both happen in plasma
50
Zero order kinetics
a constant amount of drug is cleared per unit of time.
when drugs exceed the metabolic or excretory capacity of the body to clear drugs by first order kinetics.
51
Hepatic clearance is dependent on
blood and extraction ratio
52
Hepatic extraction ratio >0.7
Perfusion-dependent elimination
increased blood flow = increased clearance
clearance will depend on hepatic blood flow.
53
Hepatic extraction ratio <0.3
Capacity dependent elimination
A decrease in protein binding or an increase in enzyme activity will increase hepatic clearance.
54
Most important organ for elimination of unchanged durgs
kidneys
55
Highly lipid soluble drugs in the kidneys
Are reabsorbed
56
Increased water solubility for a drug and Vd
Increased water solubility of drug DECREASES vd and would enhance its renal excretion
57
zero order kinetics occurs when
the plasma concentration of a drug exceeds the capacity of metabolizing enzymes.
Reflects saturation of available enzymes and results in metabolism at a constant amount of drug per unit of time.
58
Constant amount of drug metabolized per unit of time in zero order kinetics is dependent on
intrinsic activity of enzymes
59
Four Basic Pathways of Metabolism
Oxidation, Reduction, Hydrolysis, Conjugation
60
Phase I reactions of metabolism
Oxidation, reduction, hydrolysis
increase the drug's POLARITY,
61
Phase II reactions of metabolism
conjugation.
covalently link drug with highly polar molecule to make it water soluble enough for excretion
62
Hepatic microsomal enzymes are involved in
oxidation, reduction, and conjugation
63
CYP isozymes (6)
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A1
64
non-microsomal enzymes metabolize drugs mostly by
hydrolysis and conjugation
lesser degree oxidation, reduction
65
receptor occupancy theory
the more receptors occupied by a drug the more effect
66
non-receptor drug action
chelating drugs form bonds with metallic cations that may be found in body
67
Agonist drugs
bind to sites and mimic cell signaling molecules , these cause similar effects at receptors
68
Antagonist drugs
bind to receptors to prevent cell signally and block effect
69
Enantiomers can exhibit differences in
absorption
distribution
clearance
potency
toxicity (drug interactions)
70
the therapeutically inactive isomer in a racemic mixture should be regarded as
an impurity
71
efficacy
the ability of a drug to produce the desired therapeutic effect
72
potency
the relationship between the therapeutic effect of a drug and the dose necessary to achieve that effect
73
Increased affinity of a drug for its receptor
makes the drug more potent?
74
Therapeutic index of a drug
ratio of LD50 to ED50
75
commonly measured pharmacokinetic parameters of injected drugs are
elimination half time
bioavailability
clearance
volume of distribution
76
LUNG uptakes
basic lipophilic drugs
77
elimination half time and elimination half life are not equal when
the decrease in the drug's plasma concentration does not parallel its elimination from the body
78
context sensitive half time considers
the combined effects of distribution and metabolism as well as duration of continuous IV administration on drug pharmokinetics
79
rate limiting step of transdermal administration =
diffusion across the stratum corneum of the epidermis
80
Hoffman elimination / ester hydrolysis are responsible for the elimination of (4)
Succhs
atracurium
cisatricurium
mivacurium
81
metabolism is defined as
biotransformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs
82
increased water solubility of a drug reduces its
volume of distribution !
bc water soluble = ionized = in the plasma
83
fraction of total drug eliminated during first order kinetics is
independent of the plasma concentration of drug.
- attribute of the drug
84
phase I reactions...
increase the drug's polarity and prepare it for phase II
85
phase II reactions...
covalently link the drug or metabolites with a highly polar molecule that renders it more water soluble for subsequent excretion
86
hepatic microsomal enzymes are located
in the hepatic smooth ER
87
CYP-450 involved in
OXIDATION, REDUCTION, and CONJUGATION of a large number drugs
88
non-microsomal enzymes do not undergo
enzyme induction !!
which is why you can't build a tolerance to succhs
89
tachyphylaxis
tolerance that develops acutely with only a few doses of drug
90
non receptor drug action:
ex. chelating drug
91
immunity is present when
hypo-reactivity is due to the presence of antibodies
92
clearance is directly proportional to
blood flow to clearing organ
extraction ratio
drug dose
93
clearance is inversely proportional to
half-life
drug concentration in the central compartment
94
albumin binds to
acidic drugs
95
alpha1-acid-glycoprotein binds to
basic drugs
96
beta globulin binds
basic drugs
97
highly protein bound drugs typically have a slower rate of
metabolization and elimination
98
drugs cleared by zero order kinetics even in therapeutic doses
aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
99
alt. pharmacodynamics
relationship between the effect site concentration and clinical effect
100
alt. pharmokinetics
relationship between drug dose and plasma concentration
101
